Artículos (Farmacología, Pediatría y Radiología)

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The intestinal microbiome of infants with cow's milk-induced FPIES is enriched in taxa and genes of enterobacteria
(Lippincot Willkins And William; WILEY, 2024) Castro, Ana María; Sabater, Carlos; Gutiérrez Díaz, Isabel; Navarro, Sandra; Rodríguez, Silvia; Molinos, Cristina; Coronel Rodríguez, Cristóbal; Delgado, Susana; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; CSIC's Global Health Platform (PTI Salud Global); Instituto de Investigacin Sanitaria del Principado de Asturias; Spanish Ministry of Science and Innovation through the project MICROALERGYMILK; Universidad de Sevilla. CTS-995: Aspectos básicos y aplicados de la enfermedad celíaca y otras patología gastrointestinales
Objectives: Food protein-induced enterocolitis syndrome (FPIES) is a severe type of non-IgE (immunoglobulin E)-mediated (NIM) food allergy, with cow's milk (CM) being the most common offending food. The relationship between the gut microbiota and its metabolites with the inflammatory process in infants with CM FPIES is unknown, although evidence suggests a microbial dysbiosis in NIM patients. This study was performed to contribute to the knowledge of the interaction between the gut microbiota and its derived metabolites with the local immune system in feces of infants with CM FPIES at diagnosis. Methods: Twelve infants with CM FPIES and a matched healthy control group were recruited and the gut microbiota was investigated by 16S amplicon and shotgun sequencing. Fatty acids (FAs) were measured by gas chromatography, while immune factors were determined by enzyme-linked immunosorbent assay and Luminex technology. Results: A specific pattern of microbiota in the gut of CM FPIES patients was found, characterized by a high abundance of enterobacteria. Also, an intense excretion of FAs in the feces of these infants was observed. Furthermore, correlations were found between fecal bifidobacteria and immune factors. Conclusion: These fecal determinations may be useful to gain insight into the pathophysiology of this syndrome and should be taken in consideration for future studies of FPIES patients.
Perception of paediatricians and families about nutritional supplements: acceptance, tolerability and satisfaction in malnourished children (perceptiONS Jr Study)
(MDPI, 2024-07-30) Tolín Hernani, María del Mar; Miranda Cid, María del Carmen; Guerrero Cuevas, María; Álvarez Calatayud, Guillermo; Sánchez, César; PerceptiONS Jr Study Group; Millán Jiménez, Antonio; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. HUM-965: Transhumancias: hábitat, salud, patrimonio, tecnología y arte.
Background: Malnutrition is a common situation in the Spanish paediatric population. Malnourished children may benefit from different strategies, including dietary modifications or nutritional supplements (NS). It is important to know the different factors that can influence treatment tolerance and adherence, and their impact on nutrition monitoring. Objectives: To explore the perception of doctors who prescribe nutritional supplements (NS) in children and to investigate different factors involved in tolerance and adherence. Material and methods: A cross-sectional, descriptive observational study based on an ad hoc electronic survey designed to study doctors’ perceptions of at least five of their children with NS and their families, subjected to outpatient follow up. Variables included were the socio-demographic variables of the doctors and children, nutritional status of the patients, amount and characteristics of NS (hyper-caloric oral with fibre (HOFF), oral peptide (OPF) and hyper-caloric infant (HIF)), route of administration, perceived benefits, satisfaction, palatability, adherence, and acceptance. Results: 815 patients aged 0–16 years (mean 10.6 years; SD 7.8) were included. A proportion of 64% received HOFF, 16% FOP, and 20% HIF. A proportion of 84% received exclusive oral NS. Total daily calorie intake prescribed with NS ranged from 30–75% in 48.2% of cases, though it was significantly higher in children under 6 months of age. Improvement in overall condition, nutritional status and quality of life was observed in 82%, 79.5%, and 80% of subjects. Improvement in tolerance and digestive symptoms was reported in 83.5% and 72% of subjects. The degree of satisfaction and acceptance of NS was very good in 80% of cases, with taste being the most influential factor (82.3%). Adherence was adequate in more than 60%, and smell was the most significant feature in lack of adherence (55%). The flavour of the best-accepted supplement was chocolate (44%). A total of 97% of prescribing doctors would recommend the same formula again. Conclusions: In our study, prescribing doctors and families perceived an excellent benefit from the use of the prescribed formulas, improved quality of life, high satisfaction, acceptance, and adherence. The positive factors for adequate adherence were sufficient information about the formulations and their benefits, and continuity of care during follow-up. Prescribing doctors would recommend supplement use again given the perceived benefits and satisfaction.
Differences between parents’ and paediatricians’ perceptions of mild respiratory infections in childhood: contrast study
(Frontiers Media, S.A, 2024-05-09) Ortiz-Gonzalez, Luis; Delgado-Ojeda, Jesús; Guisado-Rasco, Mª Cinta; Santamaria-Orleans, Alicia; Coronel Rodríguez, Cristóbal; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. CTS-995: Aspectos básicos y aplicados de la enfermedad celíaca y otras patología gastrointestinales
Introduction: Mild respiratory infections are a common reason for consultation in paediatrics, both in the emergency department and in primary care clinics. These conditions, mostly viral and self-limiting, have a significant impact on the healthcare system, school and work absenteeism, and family routines. Despite being common and banal illnesses from a medical perspective, they involve a significant concern in families. The main objective of the contrast study was to compare the perceptions of parents and paediatricians regarding mild respiratory infections in childhood and their impact on family conciliation. Materials and methods: Two online, cross-sectional surveys were conducted among Spanish paediatricians and parents with children aged 6 months to 12 years, involving 504 paediatricians and 1,447 families, with questions on attitudes towards visits to the paediatric consultation, care burden of minor pathologies, work, and family conciliation, and treatment and prevention of these illnesses. Results: Results showed significant differences in paediatricians’ and parents’ perceptions in many aspects. According to 34.5% of paediatricians and 27% of parents, families regularly go to the paediatrician without a scheduled visit. Only 4% of parents report having self-medicated their child, while paediatricians raise this percentage significantly to 48%. Regarding the question: “it is normal for a child to have an average of 4 colds a year,” only 25.5% of the surveyed families “strongly agree” unlike to 70.2% of paediatricians. 72.8% of paediatricians “strongly agree” with: “in my opinion, it is good for children to get sick to improve their immune system” reduced to 45.9% of parents. Consultations for minor pathologies represent a “high workload” for 60.9% of paediatricians, while this opinion is agreed by only 18.9% of the parents. Conclusion: Mild respiratory infections in childhood are perceived differently by paediatricians and parents. While paediatricians perceive them as a common and manageable phenomenon, parents tend to show higher concern and demand for medical attention. This study underlines the need to improve communication between paediatricians and parents to align perceptions, optimise the use of the health system resources, and improve the efficiency in the management of these common paediatric illnesses.
Manejo diagnóstico y terapéutico de un niño afecto de una leishmaniasis visceral refractaria al tratamiento con Anfotericina B liposomal
(Sociedad de Pediatria de Andalucía Occidental y Extremadura, 2010) Olbrich, Peter; Hurtado Mingo, A.; Baltasar Navas, C.; Anchóriz Esposito, M.; Neth, Olaf; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología
El tratamiento actualmente recomendado para la Leishmaniasis visceral por L. infantum es Anfotericina B liposomal (ABL), a una dosis de 4 mg/kg durante 5 días consecutivos y una dosis de recuerdo al décimo día. Este tratamiento presenta baja toxicidad, alta eficacia y costes más bajos en comparación con otros fármacos debido a estancias hospitalarias más cortas. La PCR específica de Leishmania es una técnica reciente con alta especificidad y sensibilidad. Caso clínico: Paciente diagnosticado previamente de LV y tratado con ABL según la pauta previamente descrita con evolución clínica y analítica favorable. Reconsulta por reaparición de esplenomegalia marcada, fiebre y afectación del estado general. Serología: Leishmania IgG e IgM positivas. El resultado positivo de PCR específica de L. infantum en sangre periférica permite finalmente establecer el diagnóstico de persistencia de Leishmaniasis visceral. Recibe un segundo ciclo de ABL, añadiendo una séptima dosis al día 14 consiguiendo remisión clínica y analítica completa, sin signos de recaída durante el seguimiento. Discusión: La resistencia o respuesta incompleta al tratamiento con ABL en pacientes inmunocompetentes es infrecuente. En su caso se recomienda modificar la pauta del tratamiento añadiendo una dosis adicional el día 14 y descartar una posible coinfección con VIH. La PCR específica tiene gran utilidad en pacientes con sospecha de persistencia de infección con leishmania y pacientes inmunodeficientes ya que estos últimos presentan con cierta frecuencia falsos negativos en la serología
Disease evolution and response to rapamycin in Activated Phosphoinositide 3-Kinase delta syndrome: the european society for immunodeficiencies-Activated Phosphoinositide 3-Kinase d syndrome registry
(Frontiers Media S.A., 2018-03) Maccari, Maria Elena; Abolhassani, H.; Aghamohammadi, A; Aiuti, A,; Aleinikova, O.; Bangs, C.; Olbrich, Peter; Ehl, S.; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología
Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.
STAT1 Gain-of-Function Mutations Cause High Total STAT1 Levels With Normal Dephosphorylation
(Frontiers Media S.A., 2019-07-10) Zimmerman, O.; Olbrich, Peter; Freeman, A.F.; Rosen, Lindsey B.; Uzel, G.; Zerbe, C.S.; Rosenzweig, S.D.; Kuehn, H.S.; Holland, Stephen M.; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología
Signal transducer and activator of transcription (STAT1)1 gain of function (GOF) pathogenic variants have been associated with increased levels of phosphorylated STAT1 and STAT1-dependent cellular responses. Delayed dephosphorylation was proposed as the underlying mechanism leading to the characteristically raised pSTAT1 levels. We examined the levels of STAT1 protein and message as well as rates of STAT1 phosphorylation, dephosphorylation, and degradation associated with STAT1 GOF pathogenic variants. Fresh peripheral blood mononuclear cells (PBMC) from 14 STAT1 GOF patients carrying 10 different pathogenic variants in the coiled-coil, DNA binding, and SH2 domains and healthy donors were used to study STAT1 levels and phosphorylation (pSTAT1) following IFNγ and IFNα stimulation. STAT1 protein levels were measured by flow cytometry and immunoblot. STAT1 mRNA levels were measured using quantitative reverse transcription PCR. STAT1 protein degradation was studied using cycloheximide. Patient IFNγ and IFNα induced peak pSTAT1 was higher than in healthy controls. The velocity of pSTAT1 dephosphorylation after treatment of IFNγ stimulated CD14+ monocytes with the Janus Kinase (JAK)-inhibitor ruxolitinib was significantly faster in patient cells. STAT1 protein levels in patient CD14 + monocytes and CD3+ T cells were higher than in healthy donors. There was a strong and positive correlation between CD14+ STAT1 protein levels and peak pSTAT1 levels. Patient fresh PBMC STAT1 mRNA levels were increased at rest and after 16 h of incubation. STAT1 protein degradation was similar in patient and healthy volunteer cells. Patient IFNγ receptors 1 and 2 and JAK2 levels were normal. One patient in our cohort was treated with the oral JAK inhibitor ruxolitinib. Treatment was associated with normalization of both STAT1 protein and peak pSTAT1 levels. After JAK inhibitor treatment was stopped the patient’s CD14+ monocyte STAT1 protein and peak phosphorylation levels increased proportionally. These findings suggest that patients with STAT1 GOF mutations have higher levels of total STAT1 protein, leading to high levels of pSTAT1 after stimulation, despite rapid STAT1 dephosphorylation and normal degradation.
Primary and Secondary Immunodeficiency Diseases in Oncohaematology: Warning Signs, Diagnosis, and Management
(Frontiers Media S.A., 2019) Sánchez Ramón, Silvia; Bermúdez, Arancha; González Granado, Luis Ignacio; Rodríguez Gallego, Carlos; Sastre, Ana; Soler Palacín, Pere; ID Signal Oncohaematology Grp; Olbrich, Peter; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología
Background: Immunodeficiencies (ID), in particular primary immunodeficiencies (PID), are often associated with haematological manifestations, such as peripheral cytopenias or lymphoproliferative syndromes. Early diagnosis and management have significant prognostic implications. Secondary immunodeficiencies (SID) may also be induced by oncohaematological diseases and their treatments. Haematologists and oncologists must therefore be aware of the association between blood disorders and cancer and ID, and be prepared to offer their patients appropriate treatment without delay. Our aim was to define the warning signs of primary and secondary IDs in paediatric and adult patients with oncohaematological manifestations. Methods: A multidisciplinary group of six experts (2 haematologists, 2 immunologists, and 2 paediatricians specializing in ID) conducted a literature review and prepared a document based on agreements reached an in-person meeting. An external group of 44 IDs specialists from all over Spain assessed the document and were consulted regarding their level of agreement. Results: This document identifies the haematological and extra-haematological diseases that should prompt a suspicion of PIDs in adults and children, in both primary care and haematology and oncology departments. Cytopenia and certain lymphoproliferative disorders are key diagnostic pointers. The diagnosis must be based on a detailed clinical history, physical exploration, complete blood count and standard laboratory tests. The immunological and haematological tests included in the diagnostic process will depend on the care level. Patients who are candidates for immunoglobulin replacement therapy must be carefully selected, and treatment should be offered as soon as possible to avoid the development of complications. Finally, this document recommends procedures for monitoring these patients. Conclusions: This document combines scientific evidence with the opinion of a broad panel of experts, and emphasizes the importance of an early diagnosis and treatment to avoid complications. The resulting document is a useful tool for primary care physicians and specialists who see both adult and paediatric patients with oncohaematological diseases.
Secondary C1q Deficiency in Activated PI3K delta Syndrome Type 2
(Frontiers Media S.A., 2019) Hong, Y.; Nanthapisal, S.; Omoyinmi, E.; Olbrich, Peter; Neth, Olaf.; Speckmann, C.; Lucena, J.M.; Gilmour, K.; Genomics England Res Consortium; Zarowiecki, M.; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Instituto de Biomedicina de Sevilla (IBIS); Programa Juan Rodes, Instituto de Salud Carlos III
Monogenic forms of vasculitis are rare but increasingly recognized. Furthermore, genetic immunodeficiency is increasingly associated with inflammatory immune dysregulatory features, including vasculitis. This case report describes a child of non-consanguineous parents who presented with chronic digital vasculitis early in life, is of short stature, has facial dysmorphia, immunodeficiency (low serum IgA, high serum IgM), recurrent bacterial infections, lymphoproliferation, absence of detectable serum C1q, and low classical complement pathway activity. We identified a previously reported de novo heterozygous pathogenic splice mutation in PIK3R1 (c.1425 + 1G > A), resulting in the skipping of exon 11 of the p85α subunit of phosphatidylinositol 3-kinase and causing activated PI3Kδ syndrome type II (APDS2). This explained the phenotype, with the exception of digital vasculitis and C1q deficiency, which have never been described in association with APDS2. No mutations were identified in C1QA, B, or C, their promoter regions, or in any other complement component. Functional studies indicated normal monocytic C1q production and release, suggesting that the observed C1q deficiency was caused by peripheral consumption of C1q. Since C1q deficiency has never been associated with APDS2, we assessed C1q levels in two unrelated patients with genetically confirmed APDS2 and confirmed C1q deficiency in those two cases as well. This observation suggests C1q deficiency to be an inherent but previously unrecognized feature of APDS2. We speculate that the consumption of C1q is driven by increased apoptotic bodies derived from immune cellular senescence, combined with elevated IgM production (both inherent features of APDS2). Secondary C1q deficiency in APDS2 may further contribute to immunodeficiency and could also be associated with inflammatory immune dysregulatory phenotypes, such as the digital vasculitis observed in our case.
Influence of infant feeding on the excretion of gluten immunopeptides in feces
(Aran Ediciones S.A., 2019) Coronel Rodríguez, Cristóbal; Quero Acosta, Libia Isabel; Argüelles Martín, Federico; Guisado Rasco, María Cinta; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. CTS995: Aspectos básicos y aplicados de la enfermedad celíaca y otras patología gastrointestinales.
Introduction: the secretion of antigens from the diet into breast milk has been extensively documented. The trans fer of gliadin could be critical for the development of an immune response. Objectives: to investigate the presence of immunogenic gluten peptides in the feces of infants fed with different diets. Material and methods: a blind, prospective, controlled, col laborative study was performed in three hospitals, between September 2016 and January 2017. The study protocol was approved by the Ethics Committee of the hospitals in Seville prior to starting the study. Results: the cohort was divided into three groups of 30 infants: an experimental group (average age 9.2 ± 2.8 weeks) with exclusive breastfeeding, a control group 1 (average age 10.3 ± 3.3 weeks) exclusively fed with onset formula and a control group 2 (average age 56 ± 3.7 weeks) with infants that consumed gluten on a regular basis. The peptide 33-mer of gliadin was negative in all feces sam ples from both the experimental and control group 1. With regard to control group 2, the peptide 33-mer of gliadin was negative in 23% of cases (seven children). There was no dif ference in the amount of gluten ingested by these children compared to those who excreted the 33-mer peptide. Conclusions: the failure to detect gluten in the feces of infants that were exclusively breastfed indicates that it is probably below the limits of detection. Healthy children who consume gluten may not excrete it in feces.
Association between HLA DNA variants and long-term response to anti-TNF drugs in a Spanish pediatric inflammatory bowel disease cohort
(MDPI, 2023-01-16) Salvador-Martín, Sara; Zapata Cobo, Paula; Velasco, Marta; Palomino, Laura M.; Clemente, Susana; Segarra, Oscar; Millán Jiménez, Antonio; Merino Bohórquez, Vicente; Rodríguez, Alejandro; López Fernández, Luis Andrés; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Instituto de Salud Carlos III, España; Instituto de Investigación Sanitaria Gregorio Marañón. España; Comunidad Autónoma de Madrid; European Union (UE)
The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.
Circulating regulatory T cells from breast cancer patients in response to neoadjuvant chemotherapy
(Amer Publ Co, 2019) Sánchez Margalet, Víctor; Barco Sánchez, Antonio; Vilariño García, Teresa; Jiménez Cortegana, Carlos; Pérez Pérez, Antonio; Henao Carrasco, Fernando Manuel; Lobo Acosta, María Ángeles; Cruz Merino, Luis de la; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología
Background: Immune escape of tumor cells is a new hallmark of cancer in general, and breast cancer, in particular. Previous studies have demonstrated that the immunological profile in peripheral blood may be a prognostic and/or predictive biomarker in breast cancer. Thus, higher number of regulatory T cells (Tregs) in blood from patients with breast cancer has been reported in relation to normal donors. In the present study, we planned to evaluate the changes in different cell populations in peripheral blood: neutrophils, monocytes and lymphocytes, as well as lymphocyte subpopulations [natural killer (NK), B lymphocytes, T lymphocytes, both CD4+ and CD8+ , and Tregs] from patients with local breast cancer (both Her2+ and Her2− ), before, during and after neoadjuvant chemotherapy. Methods: We have employed flow cytometry for the cell analysis of fresh samples obtained before and whilst the neoadjuvant treatment was accomplished. We have studied 50 successive patients from the Breast Cancer Unit of the Virgen Macarena University Hospital during 2 years. Results: Neoadjuvant chemotherapy induced a significant reduction in B cells, especially in Her2− patients, and a reduction in NK cells. CD4+ T cells decreased, whereas CD8+ cells only decreased in Her2− patients. Tregs were also diminished, especially in Her2+ patients, in response to treatment. Thus, higher CD8/Treg ratio was observed in Her2+ patients. A higher percentage of Her2+ patients (66.6%) achieved complete response than Her2− patients (27.5%). Monocytes and neutrophils were not changed in peripheral blood. Conclusions: Even though the decrease in B cells and NK cells in response to chemotherapy may be deleterious in the neoadjuvant treatment of breast cancer, the decrease in Tregs and CD4 T cells, but not CD8 T cells, increasing the CD8/Treg ratio, especially in Her2+ patients, may reveal a new tool to monitor the immune response in breast cancer treated with chemotherapy in the neoadjuvant setting.
Sulforaphane reduces the chronic inflammatory immune response of human dendritic cells
(MDPI, 2023) Fernández-Prades, L.; Brasal-Prieto, M.; Alba Jiménez, Gonzalo; Martín, V.; Montserrat de la Paz, Sergio; Cejudo Guillén, Marta; Palomares, Francisca; López Enriquez, Soledad; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular
Background: Sulforaphane (SFN) is an isothiocyanate of vegetable origin with potent antioxidant and immunomodulatory properties. The characterization of its pleiotropic activity in human dendritic cells (DCs) is poorly summarized. The aim of this work was to study the immunomodulatory power of SFN in response to an inflammatory microenvironment on human monocyte-derived DCs (moDCs). Methods: We studied the immunological response induced by SFN. Apoptosis and autophagy assays were performed using flow cytometry on moDCs and a cancer cell line (THP-1). These included moDC maturation, lymphocyte proliferation and cytokine production under different experimental conditions. We investigated whether these results were associated with an inflammatory microenvironment induced by lipopolysaccharides (LPSs). Results: Our results demonstrated that SFN could interact with moDCs, significantly reducing the autophagy process and enhancing apoptosis similarly to cancer cell line THP-1 cells in a chronic inflammatory microenvironment. Under chronic inflammation, SFN modulated the phenotypical characteristics of moDCs, reducing the expression of all markers (CD80, CD83, CD86, HLA-DR and PD-L1). SFN significantly reduced the Th2 proliferative response, with a decrease in the IL-9 and IL-13 levels. Although we did not observe any changes in the regulatory proliferative response, we noted an increase in the IL-10 levels. Conclusions: These findings demonstrate that SFN exerts protective effects against LPS-induced inflammation via the modulation of moDCs/T cells towards a regulatory profile. SFN may be a potential candidate for the treatment of pathologies with an inflammatory profile.
Modulation of Beta-Amyloid-Activated Primary Human Neutrophils by Dietary Phenols from Virgin Olive Oil
(MDPI, 2023) Rivero-Pino, Fernando; Grao Cruces, Elena; López Enriquez, Soledad; Alba Jiménez, Gonzalo; Márquez Parada, Elvira; Claro Cala, Carmen María; Santa-María Pérez, Consuelo; Montserrat de la Paz, Sergio; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Ministerio de Ciencia e Innovación. España
The defense mechanism against harmful stimuli is inflammation. Indeed, neurodegenerative disorders can arise as a result of a persistent neuroinflammation. Beta-amyloid (Aβ1-42) is an early trigger in the origination of Alzheimer’s disease, leading to synaptic and cognitive impairments. Virgin olive oil (VOO) is correlated with a decreased risk of developing immune-inflammatory disorders, but the potential effects of the phenolic fraction (PF) from VOO in the modulation of neuroinflammatory processes in neutrophils remain unknown. In this study, we investigated the ability of the PF to modulate the activation of Aβ1-42-stimulated primary human neutrophils, focusing on the expression of gene and surface markers and the release of pro-inflammatory and chemoattractant mediators. Down-regulation of pro-inflammatory cytokine gene expression in Aβ1-42-treated neutrophils, among other changes, was reported. Furthermore, pretreatment with PF prevented neutrophil activation. The beneficial effects in the modulation of inflammatory responses show the relevance of VOO to achieve a healthier diet that can help prevent inflammatory diseases.
Dendritic cells as a therapeutic strategy in acute myeloid leukemia: vaccines
(MDPI, 2024-02) Palomares, Francisca; Pina, Alejandra; Dakhaoui, Hala; Leiva Castro, Camila; Munera Rodríguez, Ana M.; Cejudo Guillén, Marta; Alba Jiménez, Gonzalo; Santa-María Pérez, Consuelo; López Enríquez, Soledad; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla
Dendritic cells (DCs) serve as professional antigen-presenting cells (APC) bridging innate and adaptive immunity, playing an essential role in triggering specific cellular and humoral responses against tumor and infectious antigens. Consequently, various DC-based antitumor therapeutic strategies have been developed, particularly vaccines, and have been intensively investigated specifically in the context of acute myeloid leukemia (AML). This hematological malignancy mainly affects the elderly population (those aged over 65), which usually presents a high rate of therapeutic failure and an unfavorable prognosis. In this review, we examine the current state of development and progress of vaccines in AML. The findings evidence the possible administration of DC-based vaccines as an adjuvant treatment in AML following initial therapy. Furthermore, the therapy demonstrates promising outcomes in preventing or delaying tumor relapse and exhibits synergistic effects when combined with other treatments during relapses or disease progression. On the other hand, the remarkable success observed with RNA vaccines for COVID-19, delivered in lipid nanoparticles, has revealed the efficacy and effectiveness of these types of vectors, prompting further exploration and their potential application in AML, as well as other neoplasms, loading them with tumor RNA.
Nanomedicines and cell-based therapies for embryonal tumors of the nervous system
(Elsevier Science BV, 2022) El Moukhtari, Souhaila H.; Garbayo, Elisa; Fernández-Teijeiro, Ana; Rodríguez Nogales, Carlos; Couvreur, Patrick; Blanco Prieto, María J.; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología
Embryonal tumors of the nervous system are neoplasms predominantly affecting the pediatric population. Among the most common and aggressive ones are neuroblastoma (NB) and medulloblastoma (MB). NB is a sympathetic nervous system tumor, which is the most frequent extracranial solid pediatric cancer, usually detected in children under two. MB originates in the cerebellum and is one of the most lethal brain tumors in early childhood. Their tumorigenesis presents some similarities and both tumors often have treatment resistances and poor prognosis. High-risk (HR) patients require high dose chemotherapy cocktails associated with acute and long-term toxicities. Nanomedicine and cell therapy arise as potential solutions to improve the prognosis and quality of life of children suffering from these tumors. Indeed, nanomedicines have been demonstrated to effi ciently reduce drug toxicity and improve drug efficacy. Moreover, these systems have been extensively studied in cancer research over the last few decades and an increasing number of anticancer nanocarriers for adult cancer treatment has reached the clinic. Among cell-based strategies, the clinically most advanced approach is chimeric antigen receptor (CAR) T therapy for both pathologies, which is currently under investigation in phase I/II clinical trials. However, pediatric drug research is especially hampered due not only to ethical issues but also to the lack of efficient pre-clinical models and the inadequate design of clinical trials. This review provides an update on progress in the treatment of the main embryonal tumors of the nervous system using nanotechnology and cell-based therapies and discusses key issues behind the gap between preclinical studies and clinical trials in this specific area. Some directions to improve their translation into clinical practice and foster their development are also provided.
Estudio del impacto emocional de la pandemia por COVID-19 en niños de 7 a 15 años de Sevilla
(Asociación Española de Psiquiatría de la Infancia y la Adolescencia, 2021) Quero Acosta, Libia Isabel; Moreno Montero-Glavache, María Ángeles; León Molinari, Pedro de; Espino Aguilar, Rafael; Coronel Rodríguez, Cristóbal; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. CTS449: Estudios Neonatales
La pandemia COVID-19 ha generado cambios en las rutinas de vida, motivados por distanciamiento social y limitación de movilidad, que pueden provocar alteraciones en el estado emocional de niños y adultos tales como ansiedad y depresión, según estudios previos. Es probable que estas alteraciones permanezcan en el tiempo, aunque el estresor ya no actúe. Objetivos: valorar la salud emocional en una muestra de escolares de 7 a 15 años residentes en la ciudad de Sevilla, durante la pandemia COVID-19 en los meses de septiembre a noviembre 2020. Material y Métodos: Estudio observacional, descriptivo, multicéntrico (4 centros de reclutamiento), y transversal, aprobado por el comité local de ética. Los niños fueron seleccionados al azar simple; utilizando tabla de números aleatorios en los centros participantes a los que acudieron y en las salas de espera de dichos centros sanitarios, respondieron de manera anónima ellos solos el cuestionario Cuestionario Educativo-Clínico: Ansiedad y Depresión (CECAD) de ansiedad y depresión. Los cuestionarios fueron procesados con un programa informático diseñado para obtener los baremos en puntuaciones típicas por edades y sexo para las categorías evaluadas: ansiedad, depresión, inutilidad, irritabilidad, problemas de pensamiento y síntomas psicofisiológicos. El análisis estadístico se realizó con GNU PSPP 1.4.1-g79ad47. Resultados: La muestra del estudio incluyó 150 individuos: 77 niñas (51,3%) y 73 niños (48,7%) con una edad media de 10,85 +/- 2,01 años. El cuestionario CECAD cuantifico la media de valores de los parámetros estudiados y síntomas psicofisiológicos como normales por edad y sexo para la muestra seleccionada. Un 5% de los individuos de la muestra se catalogó como deprimidos según el punto de corte establecido, un 2 % de los individuos testados presentó ansiedad y un 10% de los escolares de la muestra elegida presentaron irritabilidad. Conclusiones: En la muestra estudiada no se observaron valores más elevados de depresión y ansiedad que en las muestras de referencia de características poblacionales parecidas a la misma. Los valores de referencia son anteriores a la era de pandemia, lo que permite informar que los niños sevillanos pertenecientes a la muestra evaluada entre 7-15 años están soportando esta compleja situación sin referir alteraciones significativas del estado emocional, hasta la fecha fin de estudio, ya que consideramos a la muestra como representativa de tal población.
Inborn errors of immunity causing pediatric susceptibility to fungal diseases
(MDPI, 2023-01-22) Olbrich, Peter; Vinh, Donald C.; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Agencia de Innovación y Desarrollo de Andalucía; Instituto de Salud Carlos III, Madrid
Inborn errors of immunity are a heterogeneous group of genetically determined disorders that compromise the immune system, predisposing patients to infections, autoinflammatory/autoimmunity syndromes, atopy/allergies, lymphoproliferative disorders, and/or malignancies. An emerging manifestation is susceptibility to fungal disease, caused by yeasts or moulds, in a superficial or invasive fashion. In this review, we describe recent advances in the field of inborn errors of immunity associated with increased susceptibility to fungal disease.
Cervical dissection diagnoses increase following endovascular treatments
(SAGE Publications, 2020) Pérez-Sánchez, S.; Domínguez-Mayoral, A.; Torres-Chacón, R. de; Gamero-García, M. Á.; Barragán-Prieto, A.; Escudero-Martínez, I.; Ocete Pérez, Rafael F.; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología
Objectives: The detection of cervical arterial dissection (CAD) has been rising in recent years owing to advanced imaging techniques. The aim of this study was to explore whether wide implementation of endovascular treatment for ischemic stroke has an impact on the diagnosis of CAD. Methods: We included all patients with CAD diagnosed at two university hospitals in Seville, Spain from January 2015 to December 2017. We collected clinical variables and information on imaging techniques used for the diagnosis. Implementation of 24 hour/365 day mechanical thrombectomy began in Seville on 15 August 2016. We compared diagnosis rates of CAD performed before and after this date. Results: We identified 41 patients with CAD. We found 13 patients diagnosed before (1.1% of all ischemic strokes) and 28 (2.2%) after implementation of neurointerventional therapy. In 17 patients, diagnosis was made in the acute phase. Dissection was not suspected according to computed tomography angiography in 11 patients owing to small dissections (n = 2) or total occlusion (n = 9). Conclusions: CAD diagnoses have been rising in recent years, essentially owing to continuous improvement in imaging techniques. Rapid access to arteriography for thrombectomy is increasing the diagnoses of CAD, even in patients with a low suspicion of dissection.
Acyclic Diterpene Phytol from Hemp Seed Oil (Cannabis sativa L.) Exerts Anti-Inflammatory Activity on Primary Human Monocytes-Macrophages
(MDPI, 2022) Claro Cala, Carmen María; Grao Cruces, Elena; Toscano Sánchez, María del Rocío; Millán-Linares, María del Carmen; Montserrat de la Paz, Sergio; Martín Rubio, María Esther; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Biología Celular
Seeds from non-drug varieties of hemp (Cannabis sativa L.) have been used for traditional medicine, food, and fiber production. Our study shows that phytol obtained from hemp seed oil (HSO) exerts anti-inflammatory activity in human monocyte-macrophages. Fresh human monocytes and human macrophages derived from circulating monocytes were used to evaluate both plasticity and anti-inflammatory effects of phytol from HSO at 10–100 mM using FACS analysis, ELISA, and RT-qPCR methods. The quantitative study of the acyclic alcohol fraction isolated from HSO shows that phytol is the most abundant component (167.59 ± 1.81 mg/Kg of HSO). Phytol was able to skew monocyte-macrophage plasticity toward the anti-inflammatory non-classical CD14+CD16++ monocyte phenotype and toward macrophage M2 (CD200Rhigh and MRC-1high), as well as to reduce the production of IL-1β, IL-6, and TNF-α, diminishing the inflammatory competence of mature human macrophages after lipopolysaccharide (LPS) treatment. These findings point out for the first time the reprogramming and anti-inflammatory activity of phytol in human monocyte-macrophages. In addition, our study may help to understand the mechanisms by which phytol from HSO contributes to the constant and progressive plasticity of the human monocyte-macrophage linage.
Nutraceuticals as potential therapeutic modulators in immunometabolism
(MDPI, 2023-01-13) Alba Jiménez, Gonzalo; Dakhaoui, Hala; Santa-María Pérez, Consuelo; Palomares, Francisca; Cejudo Guillén, Marta; Geniz, Isabel; Sobrino, Francisco; Montserrat de la Paz, Sergio; López Enriquez, Soledad; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; VII Plan Propio de Investigación y Transferencia Universidad de Sevilla, España
Nutraceuticals act as cellular and functional modulators, contributing to the homeostasis of physiological processes. In an inflammatory microenvironment, these functional foods can interact with the immune system by modulating or balancing the exacerbated proinflammatory response. In this process, immune cells, such as antigen-presenting cells (APCs), identify danger signals and, after interacting with T lymphocytes, induce a specific effector response. Moreover, this conditions their change of state with phenotypical and functional modifications from the resting state to the activated and effector state, supposing an increase in their energy requirements that affect their intracellular metabolism, with each immune cell showing a unique metabolic signature. Thus, nutraceuticals, such as polyphenols, vitamins, fatty acids, and sulforaphane, represent an active option to use therapeutically for health or the prevention of different pathologies, including obesity, metabolic syndrome, and diabetes. To regulate the inflammation associated with these pathologies, intervention in metabolic pathways through the modulation of metabolic energy with nutraceuticals is an attractive strategy that allows inducing important changes in cellular properties. Thus, we provide an overview of the link between metabolism, immune function, and nutraceuticals in chronic inflammatory processes associated with obesity and diabetes, paying particular attention to nutritional effects on APC and T cell immunometabolism, as well as the mechanisms required in the change in energetic pathways involved after their activation.

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